Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus

Joint QTL analysis of three connected F2-crosses in pigs

<p>Abstract</p> <p>Background</p> <p>Numerous QTL mapping resource populations are available in livestock species. Usually they are analysed separately, although the same founder breeds are often used. The aim of the present study was to show the strength of analysing F₂-crosses jointly in pig breeding when the founder breeds of several F₂-crosses are the same.</p> <p>Methods</p> <p>Three porcine F₂-crosses were generated from three founder breeds (i.e. Meishan, Pietrain and wild boar). The crosses were analysed jointly, using a flexible genetic model that estimated an additive QTL effect for each founder breed allele and a dominant QTL effect for each combination of alleles derived from different founder breeds. The following traits were analysed: daily gain, back fat and carcass weight. Substantial phenotypic variation was observed within and between crosses. Multiple QTL, multiple QTL alleles and imprinting effects were considered. The results were compared to those obtained when each cross was analysed separately.</p> <p>Results</p> <p>For daily gain, back fat and carcass weight, 13, 15 and 16 QTL were found, respectively. For back fat, daily gain and carcass weight, respectively three, four, and five loci showed significant imprinting effects. The number of QTL mapped was much higher than when each design was analysed individually. Additionally, the test statistic plot along the chromosomes was much sharper leading to smaller QTL confidence intervals. In many cases, three QTL alleles were observed.</p> <p>Conclusions</p> <p>The present study showed the strength of analysing three connected F₂-crosses jointly. In this experiment, statistical power was high because of the reduced number of estimated parameters and the large number of individuals. The applied model was flexible and was computationally fast.</p

Joint QTL analysis of three connected F2-crosses in pigs

Mapping Quantitative Trait Loci (QTL) has received considerable attention in livestock genetic research over the last two decades. Knowledge of the location, the mode of inheritance and the size of effects of QTL contribute to a deeper understanding of the genetic architecture of quantitative or complex traits. Furthermore, mapped QTL were envisaged for use in so-called marker assisted selection programs. Before the era of genomics started, microsatellites were usually used as genetic markers for QTL mapping. In pigs, F2-crosses were frequently established from divergently selected founder breeds. Usually, the sizes of these F2-experiments are in the range of 300 individuals, which is too small to obtain sufficient statistical power to map QTL precisely. One large F2-experiment was set up in the 90th of the last century at the University of Hohenheim. Three F2-crosses from three genetically different founder breeds (Meishan, Pietrain and European Wild Boar) with almost 1000 individuals were genotyped and phenotyped for around 50 quantitative traits. In further studies, each of the crosses were analysed separately and more complex modes of inheritance were ignored. However, several researchers showed that a combined analysis with several QTL experiments can boost statistical power. Additionally, the mode of inheritance is sometimes not restricted to additive and dominant gene action. The overall aim of this thesis was the joint analysis of these three F2-crosses with more appropriate statistical models and to draw more precise conclusions about the QTL segregating within these experimental designs.Die Kartierung von chromosomalen Bereichen mit einem Einfluss auf die Varianz eines quantitativen Merkmals (quantitaitve trait loci / QTL) hat im Bereich der Nutztierhaltung im Laufe der letzten Jahrzehnte erheblich an Bedeutung gewonnen. Das Wissen über die Position, den Erbgang und die Größe der QTL-Effekte führt zu einem besseren Verständnis der genetischen Architektur quantitativer Merkmale. Darüber hinaus werden die kartierten QTL in so genannten markergestützten Selektionsprogrammen eingesetzt. Vor Beginn des Genomik-Zeitalters wurden Mikrosatelliten als genetische Marker zur Kartierung der QTL genutzt. Zur Kartierung von QTL bei Schweinen wurden häufig F2-Kreuzungen erstellt. Diese entstanden aus genetisch divergent selektierten Elternlinien. Üblicherweise war die Zahl der F2-Nachkommen nicht sehr hoch und lag bei etwa 300 Individuen. Diese Anzahl an Nachkommen ist zu gering um statistisch genügen Aussagekraft zu haben um QTL genau zu kartieren. An der Universität Hohenheim wurde in den 90er Jahren ein großes F2-Kreuzungsexperiment gestartet. Hierbei wurden drei F2-Kreuzungen aus drei genetisch verschiedenen Elternlinien (Meishan, Pietrain und europäisches Wildschwein) gezüchtet. Die Nachkommenzahl lag bei rund 1000 Tieren. Diese wurden für etwa 50 Merkmale phänotypisiert. In früheren Studien wurden diese Kreuzungen separat ausgewertet und komplexere erbliche Zusammenhänge wurden hierbei außer acht gelassen. Verschiedene Forschergruppen zeigten, dass die Auswertung verschiedener QTL Experimente in einer gemeinsamen Analyse die statistische Aussagekraft deutlich erhöht. Zudem wurde gezeigt, dass der Erbgang der QTL häufig nicht rein additiv ist. Ziel dieser Arbeit war die gemeinsame Analyse dieser drei F2-Kreuzungen mit einer für den datensatz zugeschnittenen Methode, welche auch komplexere erbgänge der QTL berücksichtigt

Der Einsatz von Öko-Produkten in der Außer-Haus-Verpflegung (AHV): Status Quo, Hemmnisse und Erfolgsfaktoren, Entwicklungschancen sowie politischer Handlungsbedarf

Ziel des Forschungsvorhabens war es, hinsichtlich einer Stärkung und Förderung ökologischer Produkte in der Außer-Haus-Verpflegung (AHV), repräsentative Daten und verlässliche Ergebnisse zu gewinnen, die die aktuelle Situation darstellen und eine Entscheidungsgrundlage für zielgerichtete Fördermaßnahmen bilden. Dazu wurde eine repräsentative schriftliche Befragung bundesweit mit Entscheidungsträgern der Gemeinschaftsverpflegung und eine telefonische Umfrage mit Akteuren der Individualverpflegung durchgeführt. Öko-Produkte kommen in 31 % der Einrichtungen der Gemeinschaftsverpflegung und in 21 % der Gastronomiebetriebe zum Einsatz. Der ermittelte Anteil an Öko-Produkten am Lebensmitteleinsatz in der Gemeinschaftsverpflegung beläuft sich auf 8 % und auf 5 % in der Individualverpflegung. Der Einsatz von Öko-Produkten bewährt sich am stärksten, wo Motivallianzen zwischen „Ökologie“ sowie „Gesundheit“ oder „Zukunftssicherung“ zu finden sind. In der AHV werden Öko-Produkte vorrangig in Form von Komponenten, aber auch als Öko-Gerichte oder Menüs eingesetzt. Neben der Datenanalyse wurden Best-Practice-Beispiele mit einem qualitativen Forschungsansatz untersucht. Besonders bewährt hat sich der Einsatz von Öko-Produkten, wenn dieser (1) in ein ganzheitliches Konzept mit Motivallianzen und zielgruppenspezifische Angeboten integriert ist, (2) die Einführung schrittweise erfolgt, (3) der Mitarbeitermotivation eine hohe Aufmerksamkeit zukommt, (4) Einrichtungsleitung und Mitarbeiter das Vorhaben unterstützen, (5) dem Mehrpreis von Öko-Lebensmittel durch sinnvolle Preisstrategien begegnet, (6) eine aktive Kundenkommunikation betrieben wird, (7) bedarfsgerechte Lieferangebote und vertrauensvolle Verhältnisse zu Direktvermarktern/Lieferanten bestehen. Abschließend wurden modulare Optimierungs- und Umsetzungsstrategien die Preis-, Distributions-, Produkt- und Kommunikationspolitik sowie Checklisten für verschiedene Akteure der AHV entwickelt

Allele-Dependent Similarity between Viral and Self-Peptide Presentation by Hla-B27 Subtypes

Molecular mimicry is discussed as a possible mechanism that may contribute to the development of autoimmune diseases. It could also be involved in the differential association of the human major histocompatibility subtypes HLA-B(*)2705 and HLA-B(*)2709 with ankylosing spondylitis. These two subtypes differ only in residue 116 of the heavy chain (Asp in B(*)2705 and His in B(*)2709), but the reason for the differential disease association is not understood. Using x-ray crystallography, we show here that the viral peptide pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236-244) of Epstein-Barr virus) is presented by the B(*)2705 and B(*)2709 molecules in two drastically deviating conformations. Extensive structural similarity between pLMP2 and the self-peptide pVIPR (RRKWRRWHL, derived from vasoactive intestinal peptide type 1 receptor (residues 400-408)) is observed only when the peptides are presented by B(*)2705 because of a salt bridge between Arg(5) of both peptides and the subtype-specific heavy chain residue Asp(116). Combined with functional studies using pLMP2/pVIPR-cross-reactive cytotoxic T cell lines and clones, together with target cells presenting these peptides or a modified peptide analogue, our results reveal that a pathogen-derived peptide can exhibit major histocompatibility complex class I subtype-dependent, drastically distinct binding modes. Furthermore, the results demonstrate that molecular mimicry between pLMP2 and pVIPR in the HLA-B27 context is an allele-dependent property

An artificial intelligence algorithm is highly accurate for detecting endoscopic features of eosinophilic esophagitis

The endoscopic features associated with eosinophilic esophagitis (EoE) may be missed during routine endoscopy. We aimed to develop and evaluate an Artificial Intelligence (AI) algorithm for detecting and quantifying the endoscopic features of EoE in white light images, supplemented by the EoE Endoscopic Reference Score (EREFS). An AI algorithm (AI-EoE) was constructed and trained to differentiate between EoE and normal esophagus using endoscopic white light images extracted from the database of the University Hospital Augsburg. In addition to binary classification, a second algorithm was trained with specific auxiliary branches for each EREFS feature (AI-EoE-EREFS). The AI algorithms were evaluated on an external data set from the University of North Carolina, Chapel Hill (UNC), and compared with the performance of human endoscopists with varying levels of experience. The overall sensitivity, specificity, and accuracy of AI-EoE were 0.93 for all measures, while the AUC was 0.986. With additional auxiliary branches for the EREFS categories, the AI algorithm (AI-EoE-EREFS) performance improved to 0.96, 0.94, 0.95, and 0.992 for sensitivity, specificity, accuracy, and AUC, respectively. AI-EoE and AI-EoE-EREFS performed significantly better than endoscopy beginners and senior fellows on the same set of images. An AI algorithm can be trained to detect and quantify endoscopic features of EoE with excellent performance scores. The addition of the EREFS criteria improved the performance of the AI algorithm, which performed significantly better than endoscopists with a lower or medium experience level

Selbstbestimmt und gut versorgt im Alltag

2021 wurden in der Kernstadt Fulda 2000 Personen über 65 Jahren postalisch zu ihrem Alltag und ihrer Lebensgestaltung befragt. In einem Überblick über unterschiedliche Lebensbereiche wird das Bild der Alltagsversorgungsmöglichkeiten und -hindernisse älterer Menschen deutlich. Handlungsempfehlungen für soziale und kommunale Unterstützung ergänzen die Zahlen

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Rhodococcus erythropolis BG43 genes mediating Pseudomonas aeruginosa quinolone signal degradation and virulence factor attenuation

Müller C, Birmes FS, Rückert C, Kalinowski J, Fetzner S. Rhodococcus erythropolis BG43 genes mediating Pseudomonas aeruginosa quinolone signal degradation and virulence factor attenuation. Applied and Environmental Microbiology. 2015;81(22):7720-7729